Week 1: Tree structures, Sets, and Descent
Note: I’ve added some extra links based on questions I couldn’t answer during the lectures. These added materials are in green.
There are two very basic ideas which are the foundations of biology. The first is Darwin’s idea, that all organisms are related by descent from common ancestors. They differ by inherited mutations, producing hierarchical tree-like structures of relatedness. In the first week of this course, we will explore the structure of biological molecules (particularly nucleic acids and proteins) with this idea firmly in mind.
Day 1
Read MIT chapters Chemistry Review and Cell Biology, subsections 1-7, Read Stryer Chapter 2: Biochemical Evolution
Learning Objectives: 1) To understand why carbon is uniquely suited to build large complex molecules needed to support life. 2) To understand why liquid water is uniquely suited as a medium for biological chemistry. 3) To see that life must have arisen in a series of steps, from small simple organic molecules through self-replicating RNAs to the current form of membrane-bound cells full of DNA libraries and protein industrial machinery.
Tree structures

phylogeny vs. ontogeny
tree of life (berkely link)--one ancestor species, each species expresses genes which have diverged over time.
cell fate lineage (wormatlas.org) --one ancestor individual, each cell expresses only a subset of inherited genes.
analogies to number sets
Origins of Life
why carbon? (WebElements)
Boron: electron deficient
Nitrogen: too electron rich (N-N bond ~ 171kJ/mol)
C-C ~ 348kJ/mol
too big (Si-Si bond ~ 177kJ/mol)
too stable (Si-O bond ~ 369kJ/mol)
Phosphorus: less stable than nitrogen
reducing environments and redox reactions
precursors of life
redox history
chemical evolution (Stryer timeline)
the RNA world
membranes and compartments
Aqueous Solutions
hydrogen bonding
water molecule
in liquid water
hydrophilic vs. hydrophobic
acids and bases
titrations & buffers (Voet Ch2)
amino acids--glycine (Voet Ch4)
3 laws
energy OF THE WHOLE UNIVERSE is conserved
entropy OF THE WHOLE UNIVERSE always increases
entropy of a perfect crystal at 0K is 0
Gibb’s free energy
state functions (temperature, pressure, volume, ENERGY)
enthalpy (NASA link)
spontaneity (sch4u link)
chemical equilibrium
Day 2
Read Stryer Chapter 4: Exploring Proteins , Stryer Chapter 6: Exploring Genes
Learning Objective: Before accepting the numbers some experimentalist has generated into our favorite model, we’d like to have some idea as to how he generated them. Today, we’ll discuss a few particular techniques that relate to the laboratory section of the course.
Techniques of Purification
opening cells
mechanically (with a blender or by freezing)
with enzymes (Voet Ch 15) (ProteinDataBase)
separating components (Voet Ch6)
by size
by charge
by affinity
read MIT chapter Large Molecules
The four major classes of large molecules have similar chain-like structures, built up from smaller repeating units. We want to compare the similarities and differences between these classes of molecules, because differences in structure mean differences in function. First, we should talk about the nature of the chemical bonds that link the chain-like molecules together.
Learning Objectives: 1) To understand why only covalent bonds (and not ionic or hydrogen bonds) are stable in liquid water, where life happens, and why some bonds are more stable than others. 2) To see how the modular nature of these molecules leads to huge possible diversity. 3) To understand that creating long ordered molecules, decreasing their entropy, requires the input of energy.
Covalent Structures of Bio-polymers
what is a covalent bond?
comparison with ionic bonds
electronegativity defined
electronegativity in the periodic table
molecular orbitals
linking and breaking chains of molecules: condensation and hydrolysis
nucleic acids (phosphodiester bonds) delta G ~ +25kJ/mol
4 monomers (MIT nucleic acids)
RNA pol 1 (Stryer Fig 28.1)
glycosidic linkages (MIT carbohydrates) delta G ~ +15kJ/mol
branched carbohydrates (Stryer Fig11.2)
proteins (peptide bonds) deltaG ~ +10kJ/mol
20 monomers (MIT amino acids)
mechanism (Stryer Fig 29.3)
types (MIT lipids)
synthesis more complicated
Day 3
Yesterday in the lab we evolved some bacteria. We took a population of (nearly) identical bacteria and created variation by intoducing a plasmid containing foreign genes. This variability can be inherited or preserved across generations. Then we created a selection pressure by plating the bacteria on plates containing the antibiotic ampicillin. These three conditions are all that evolution requires. Today we’re going to look at the mechanisms by which variability is created naturally. These include the copying of DNA, an error-prone process, and the shuffling of whole genes between organisms.
Learning Objectives: 1) To understand that mutations are necessary for proteins to evolve, or adapt to a changing environment. 2) To understand that DNA replication, while error-prone, has proofreading mechanisms. In other words, current mechanisms of DNA replication are a compromise between perfect copying and unlimited mutation. 3) To understand that recombination or shuffling of existing genes is a safer and faster method of introducing variation into a population.
read Stryer Chapter 7: Exploring Evolution
Sequencing & Measuring Relatedness
sequencing reactions from NCGR
reconstruction of genomes
comparing sequences (Stryer Conceptual Insights, click Sequence Analysis)
DNA Repair & Recombination
DNA Repair, and why no Uracil in DNA? Short answer, because uracil is a relic in RNA. RNA is degraded too soon for C to turn into U with any dangerous frequency, therefore no need to replace U with T.
in bacteria (Kaiser’s microbiology page)
crossing over during diploid meiosis from Access Excellence
mobile genetic elements
Day 4
Yesterday we talked about heredity and variation, two of the three things needed for evolution to work. Both of those factors are embodied in DNA. Today we will talk about how the information contained in DNA is turned into proteins, which are in all known biological cases the site of selection, meaning that proteins directly determine whether you live and reproduce or become a genetic dead end. It’s not impossible for selection to act on a nucleic acid (for an imaginary example see Stryer Fig7.23), and perhaps early in evolution selection did act directly on nucleic acids.
Learning Objectives: 1) To understand the flow of information from DNA through RNA to proteins. 2) To understand how the opposed processes of making and degrading proteins compete, leading to fine control over the number of molecules of any particular protein at any particular time.

read MIT chapter Central Dogma
making RNA (RNA polymerase) (Stryer Ch28.1)
initiation (Stryer Fig5.4)
promoters with more G-C content are transcribed less often
elongation (stryer Fig5.25)
termination (Stryer Fig5.28)
postprocessing in prokaryotes
postprocessing in eukaryotes (Lodish Fig11.7, click the Q to watch a cool little movie)
why are there introns? (read Genomes Ch15.32)
alternate splicing in eukaryotes (Cooper Fig6.46) (Stryer Ch28.4) (Kenyon link)
Translation (protein synthesis cartoon)
three roles of RNA (Lodish Fig4.4)
the message, mRNA
the ribosome, rRNA (Stryer Ch29.3)
the adaptor, tRNA (ProteinDataBank tRNA) (Lodish Fig4-26)
initiation sequences (Stryer Fig29.20)
methionine (Lodish Fig4.5) (Stryer Fig29.26)
initiation (Lodish Fig4.5.1)
elongation (Lodish elong movie)
termination (Lodish Fig4.5.3)
post-translational modification
protein cleavage (Stryer Ch10.5)
side chain modifications
cysteine disulfide bonds (Stryer Fig3.21)
glycosylation (Stryer Ch11.3.1)
acetylation of histones (Lodish Fig10.58)
phosphorylation (Cooper fig13.22)(Stryer Ch10.4)
protein degradation
lysosomes are full of nonspecific proteases
ubiquitin (Lodish Fig3.18)
N terminal residues partly determine half-life; note that these are not grouped as in the property table (MIT Large Molecules). Leu, Ile, and Gly are all small and hydrophobic, yet they span the range.
Met, Ser, Ala, Thr, Val, Gly > 20 hours
Ile, Glu, Tyr, Gln ~ 20-30 minutes
Phe, Leu, Asp, Lys, Arg ~ 2-3 minutes

Day 5
So far we’ve been talking about one-dimensional polymers, chain-like molecules which carry information in their sequences. Today we go beyond sequence to talk about the three-dimensional structure of nucleic acids and proteins. Yesterday in the lab we saw that adding one protein chain (beta-lactamase) allowed bacteria to live in the presence of deadly ampicillin, while another protein chain (GFP) caused them to glow green. How can just 20 amino acids do so many different things?
Learning Objectives: 1) To understand that sequence determines structure and structure determines function. Structure of DNA determines when and how often a gene will be transcribed, while structure of a protein determines what cellular activity that protein will have. 2) To understand the relationships between the four levels of protein structure. 3) To see that although the gene is the unit of heredity, genes themselves are modular, made up of domains that are only obvious when one examines the protein.
read Stryer Chapter 3: Protein Structure and Function
3-D structure of DNA and RNA
supercoils and regulation by access
single nucleosome
chromatin packing
3-D structure of proteins shows hierarchy (Lodish Fig3.4)
amino acid reminder (Lodish Fig3.2)
why these 20? (Stryer Fig3.17)
secondary structure
tertiary structure, or folding and function
spontaneous folding (Lodish Fig3-13) (Stryer Fig3-58)
assisted folding (Lodish fold movie)
binding a small ligand (cAMP)
functional domains within a single polypeptide chain (Lodish Fig3-10)
Do exons line up with domains? (Genomes Fig15.19)
short peptide sequences (Stryer Fig3.55)
quaternary structure, or multiple-subunit proteins (Stryer Ch3.5)
structural evolution (Lodish Fig3-12)
silent mutations
base substitutions (Stryer Table5.4)
amino acid substitutions
why not sequence proteins?
proteins can’t replicate themselves
you’d miss all the regulatory sequences (promoters, etc.)
case study: Green Fluorescent Protein
physics of fluorescence from Molecular Probes
PDB molecule of the month GFP
GFP structure from Fan Yang at Rice